Cyclosporin A (CAS Registry Number: 59865-13-3) is a widely recognized immunosuppressive agent and naturally occurring fungal metabolite. Cyclosporin A is the first identified member of the cyclosporin family of poly-N-methylated cyclic undecapeptides having the following structure:

As shown by the structure above, Cyclosporin A consists of 11 amino acids and can be further represented as follows:

wherein:
MeBmt is (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine;
αAbu is L-α-aminobutyric acid;
Sar is sarcosine;
MeLeu is N-methyl-L-leucine;
Val is L-valine;
Ala is L-alanine;
DAla is D-alanine; and
MeVal is N-methyl-L-valine.
The numbers 1-11 are used to designate each of the eleven amino acids. Thus, for example, MeBmt is the amino acid at position 1; sarcosine, the amino acid at position 3. In certain instances, the description herein may refer to the amino acid side chain at any one of positions 1-11. The carbon to which the amino acid side chain is attached is referred to as the alpha (a) carbon.
Cyclosporin B is identical to Cyclosporin A except that αAbu is replaced by L-alanine. Cyclosporin C is identical to Cyclosporin A except that αAbu is replaced by L-threonine. Cyclosporin D is identical to Cyclosporin A except that αAbu is replaced by L-valine. Cyclosporin G is identical to Cyclosporin A except that αAbu is replaced by (S)-2-aminopentanoic acid.
Cyclosporin A is best known for its immunosuppressive properties and is commonly prescribed for use in patients that have undergone bone marrow or organ transplantation.
The intracellular receptor targets of Cyclosporin A are the cyclophilins. Cyclophilin proteins exhibit peptidyl-prolyl cis-trans isomerase (PPIase) activity, which catalyzes cis-trans isomerization of peptide bonds preceding proline, and play functional roles in chaperoning and protein folding. The immunosuppressive activity for which Cyclosporin A is so well known does not directly result from inhibiting cyclophilin activity. Rather, a Cyclosporin A-cyclophilin A complex inhibits the Ca2+/calmodulin-dependent phosphatase calcineurin, thereby suppressing T-cell proliferation by interfering with downstream signal transduction. (See J. Lee and S. S. Kim, Journal of Experimental & Clinical Cancer Research, 2010, 29:97; J. W. Elrod and J. D. Molkentin, Circulation Journal, 2013, 77:1111; C. Piot, et al., New England Journal of Medicine, 2008, 359:473.)
The present invention relates to the surprising discovery of water-soluble, non-immunosuppressive analogs of Cyclosporin A that are potent inhibitors of cyclophilin A.